Which FT3, FT4 and TSH levels have the highest and lowest prevalence rates for 10 common health disorders?
- Hyperlipidemia (high cholesterol)
- Coronary artery disease
- Heart failure
- Atrial fibrillation
- Peripheral vascular disease
- Renal failure (kidney failure)
Is high-normal TSH and low FT3 associated with one condition, while high-normal FT4 and low or high TSH strongly associated with another condition?
Or do they all have a generally similar pattern of strong disease associations with certain thyroid hormone levels?
Anderson et al, 2020 collected data from the medical charts of 174,914 adults from 1999 to 2018 and associated their diagnoses at the time of their FT4, TSH, and FT3 thyroid laboratory tests.
The researchers provided this rich treasure trove of data in appendix tables. However, their article focused only on atrial fibrillation risk and singled out the FT4 hormone because of their chosen data analysis methods.
Here I bring Anderson and team’s appendix data set into focus through visual and verbal analyses their article had no time or space to provide.
In the 10 data tables, the visual patterns will jump out through heat maps that color-code higher and lower prevalence rates in a grid of 18 hormone categories (6 levels per hormone x 3 hormones).
Each disease’s table comes with a scientific discussion of its puzzles and patterns that you can click to expand. Read quotations from other scientists that noticed similar patterns and commented on them.
At the end, tables summarize rankings of prevalence rates: One gives the average rank of prevalence rates across all 10 disorders and the other focuses on 4 cardiovascular disorders.
What can we learn from this comparison?
- Normal TSH levels rarely associated with the lowest rates of these disorders, which is unexpected given prevailing beliefs about the safety of normal TSH.
- Abnormally high or low TSH categories rarely had the highest prevalence rates for these disorders, which is also unexpected for the same reason.
- Instead, FT4 and FT3 levels usually had the highest and lowest prevalence rates.
- TSH and FT4 levels in high-normal range often had higher prevalence rates than extremely high or low levels, which is puzzling.
- FT3 and FT4 prevalence rates often trended in the opposite direction from each other. This shows that the human body responds differently to these two forms of thyroid hormone in circulation.
- Hormone categories with lower average FT3:FT4 ratios often correlated with higher disease prevalence rates. Therefore, the hormone relationships matter, not just their levels.
Why has it been so difficult for scientists and doctors to see these patterns emerge in disease prevalence rates? What are the implications of long term medical blindness to the power of FT3 levels and FT3:FT4 ratios in human health? What do the data mean for treated thyroid patients? I’ll give some suggestions for action.
Copyright fair dealing note
How did Anderson and team obtain their data?
In a health care region in the northwestern United States, medical records between 1999 and 2018 were searched.
- Adults over 18 years old, 174,914 were chosen if they had a FT4 lab test and were not treated with thyroid medications. The date of this FT4 test was considered their “study entry” date.
- Among these people, 147,834 had a TSH test within 60 days of their study entry.
- Among these people, 26,524 also had a FT3 test within 60 days.
On average, people had one, two, or three of these these tests within a period of only 2 days.
The population’s official diagnostic codes for atrial fibrillation and 9 other chronic diseases at the time of this set of tests were recorded. Therefore, the research team tabulated disease association rates with each subcategory of hormone levels.
Anderson’s article, titled “Free thyroxine within the normal reference range predicts
risk of atrial fibrillation,” focused on one disorder — atrial fibrillation (AF).
Why are these unadjusted prevalence rates worthy of analysis?
For advanced scientific readers: Click to expand
How to read Anderson’s data
In the tables below, each hormone has six levels from low to high:
- Normal Q1,
- Normal Q2,
- Normal Q3,
- Normal Q4,
The four divisions within in reference range are “quartiles.”
The reference ranges were:
- FT4: 0.75 to 1.50 ng/dL
- TSH: 0.54 to 6.80 mcIU/L (Units equal to mU/L; 0.4 to 4.0 is more common.)
- FT3: 2.40 to 4.20 pg/mL (100x smaller than the usual unit for FT3, pg/dL)
Where do the 4 Quartiles fit within reference range?
Anderson and team put all the people with “Normal FT4” and divided them into four equal sized groups, and did the same for the other two data sets. Dividing data into (3) tertiles, (4) quartiles or (5) quintiles is standard practice.
This resulted in each group covering a different portion of each reference range.
- Notice the pink gridlines representing the reference ranges for the hormones.
- Notice the size of Q4 on the right hand side of the diagram. Anderson’s “Normal Q4” quartile encompassed most or all of the upper half of reference range for each hormone. Q1, Q2, and Q3 cover narrower regions in the lower half of the reference ranges.
The TSH upper limit is controversial. In the region of the US where the study was conducted, the TSH limit was raised significantly near the very end of the study period. Their “Normal Q4” includes TSH values up to 6.80 mIU/L. (See “Details on methods” below). This means that some people with subclinical hypothyroidism were misclassified in Normal Q4.
Caution: These data are only from people on NO thyroid therapy.
The following prevalence rates are associations found in UNtreated individuals.
These associations cannot translate to simple prescriptions for treated thyroid patients’ hormone levels.
Thyroid disease and its treatments distort TSH-FT4-FT3 hormone relationships.
The prevalence rates you see below will be different in various populations of treated thyroid patients on different thyroid hormone treatments — levothyroxine (LT4), liothyronine (LT3), porcine desiccated thyroid, and combinations.
There is no simple way to prevent risk in a hormone-treated person whose FT3:FT4 ratio is abnormal and TSH-FT3 relationship is abnormal during thyroid therapy. In some patients, the HPT axis is untrustworthy, and TSH is lower than it should be per unit of FT4 and FT3 because of dysfunctional TSH secretion.
Therefore, chronic disease prevalence research, risk assessment and therapy decisions must be approached with great caution and respect for adaptation to individual thyroid disabilities.
The 10 chronic disorders
Hypertension prevalence rates: Discussion
Hyperlipidemia prevalence rates: Discussion
Depression prevalence rates: Discussion
Diabetes prevalence rates: Discussion
5. Coronary artery disease (CAD)
CAD prevalence rates: Discussion
6. Heart failure
Heart failure prevalence rates: Discussion
7. Atrial fibrillation
Atrial fibrillation (AF) prevalence rates: Discussion
8. Peripheral vascular disease (PVD)
PVD prevalence rates: Discussion
9. Renal failure
Renal failure prevalence rates: Discussion
Dementia prevalence rates: Discussion
For each of the 10 disorders, the 18 hormone level categories were ranked from lowest (1) to highest per set, using repeated numbers (5,5,5) when the prevalence rates were identical in two hormone level categories. This was the result:
The boldest colors are in the bottom row. FT3 spans an average prevalence rate ranking from 13.8 to 2.2. The difference between Low FT3 and Normal Q1 FT3 is almost double.
Beyond FT3, the secondary hot spot is TSH in Normal Q4, and the secondary cold spot is High FT4.
Narrowing down the ranking summary to focus only on 4 chronic cardiovascular diseases yields a similar pattern:
FT3 is still the most intense row. Now the step from Low FT3 to Normal Q1 is 3x the distance in the ranking of prevalence rates. High-normal TSH is still the next hot spot.
Now the red color is more evenly distributed. Notice that the 3 types of hypothyroidism (low FT4, high TSH, low FT3) are color coded red.
Why do doctors associate hyper with cardiovascular symptoms and tend to ignore the association with hypo?
These 10 chronic diseases cost our health care systems a lot of money and can cause great human suffering over a lifetime.
We can’t afford to separate thyroid hormone levels from chronic disease when they give us such major clues about how to manage these diseases more wisely.
Here are some suggested action items:
- Distinguish acute from chronic Low T3 syndrome (NTIS)
- Treat and prevent low T3 syndrome.
- Stop excluding thyroid patients from NTIS study and treatment.
- Call for a T3 paradigm shift in thyroid science
1. Distinguish acute from chronic Low T3 syndrome (NTIS)
The data say nothing about the duration of low T3 syndrome, but 15% of the FT3-tested population fit in that category.
The acute (and often benign) phase of NTIS must be distinguished from the pathological state of chronic low T3 that demonstrates a critical failure to recover a vital hormone supply (Moura Neto & Zantut-Wittmann, 2016; Van den Berghe, 2014).
Chronic low Free or Total T3 and chronic low T3:T4 ratios are not just effects of illness, but can also become pathological drivers and maintainers of illness.
Many decades of research in NTIS have shown that a weak TSH response and/or thyroid gland response can perpetuate a low Total or Free T3 level and T3:T4 ratio, leading to increased rates of poor health outcomes and death. (NOTE: In severe illness, the Total T3 is often used instead of Free T3 because some illnesses and blood thinners like heparin can artificially inflate Free hormone test results.)
Look at the T3:FT4 ratios of people with heart failure:
“Lower levels of total T3 were well correlated with 1-year HF in PCI-treated AMI patients. The T3/fT4 levels can be an additional marker to predict HF.”Kang et al, 2017
The chronic low T3 levels and T3:T4 ratios during chronic disease are prognostic of future problems.
This is the case in many types of chronic illness including renal failure, cardiovascular diseases, not just in acute conditions demanding intensive care (Ataoglu et al, 2018). (See our review of Ataoglu: Low T3 in critical illness is deadly, and adding high T4 is worse.)
2. Treat and prevent chronic low T3 syndrome.
Enough research has catalogued the high rates of death and morbidity in Low T3 Syndrome (also called mistakenly called “euthyroid sick syndrome” just because TSH usually remains normal).
Yet publications continue to repeat the skeptical medical stasis that
“no clear consensus has emanated from clinical studies”
of thyroid hormone interventions, so
“many scholars suggest that treatment of the primary disease takes precedence over ESS [euthyroid sick syndrome] intervention.”Wang et al, 2018
However, quotes like these reveal an arbitrary, false division between the “primary disease” (such as heart failure) and a thyroid hormone metabolism disorder such as ESS, when thyroid hormone signaling clearly modifies primary disease outcomes.
Thyroid scientists with courage have previously advocated for more NTIS treatment trials involving T3 (DeGroot, 2006), but it seems to have fallen on deaf ears. The considerations of treatment are complex, but few have the courage to face them for the sake of saving lives, health care dollars, and human suffering.
If we supply ventilators and oxygen to people who cannot breathe, then it is unethical not to assist the thyroid-healthy human body to recover healthy FT3 levels and FT3:FT4 ratios to prevent the progression of a chronic disease.
Patients with chronic diseases deserve to access FT3 thyroid hormone levels and ratios that are conducive to their recovery.
3. Stop excluding thyroid patients from NTIS study and treatment
This research by Anderson and team unfortunately excluded from their main data set all people dosed with thyroid hormone because of our complexity.
There were 37,288 people excluded from Anderson’s study for this reason. No data tables were provided for them, no explanation of their quartile divisions, and no FT3 or TSH prevalence data was provided. We were only given a verbal summary of the FT4 odds ratios that the researchers felt were most important as they looked for linear trends within the reference range.
This is a significant loss of data. We have insufficient knowledge of a neglected population.
It is very disturbing that thyroid patients are routinely excluded from low T3 syndrome / nonthyroidal illness (NTIS) research, as we’ve discused in previous posts.
As a result, only a handful of small-scale studies have examined NTIS in treated patients, one of them a biased study of 6 men on Synthroid who underwent NTIS after surgeries. This study only proved that treated patients are not immune to the biochemical phenomenon of Low T3 Syndrome.
It cannot reassure any reasonable reader that patients on LT4 monotherapy will, on average, recover at the same rate as untreated people with healthy thyroids.
Consider the cruelty and irresponsibility of this research exclusion. Treated thyroid patients are a more medically vulnerable cohort than the health-thyroid population. Their hormones and TSH are medically manipulated, not naturally acquired and metabolized partly by a healthy thyroid gland, now removed, that once expressed most of the Dio1 and Dio2 enzymes in their body. Even at a normalized TSH, their Free T4 and Free T3 are not likely to be adjusted in the way a normal healthy TSH-thyroid partnership would configure them.
Presuming that a treated, thyroid-disabled person’s TSH-FT4-FT3 configuration is risk-free is like presuming that a woman without a man’s traditional symptoms of heart attack is not at risk of having a heart attack.
Unfortunately, medical schools do not routinely teach the narrow index of individuality (IOI) in thyroid hormone reference ranges that exists even in untreated people. As a result, many patients are forced to suffer for decades with thyroid hormone levels and ratios ill-suited to their individual metabolic needs while a therapy lacking any T3 manipulates their TSH to suit current medical opinion. An unintended pharmaceutical T3-ectomy may be the price of obtaining the target TSH concentrations that a doctor naively believes signifies euthyroidism for every human being.
- Will their chronic low-normal Free T3, high-normal Free T4 and high-normal TSH take advantage of a familial susceptibility for renal failure, hastening its progression to stage 4 despite treatment?
- How will their renal failure further lower their FT3 and plunge them into nonthyroidal illness (NTIS)?
- How can they ever recover enough FT3 to support kidney and cardiac function if they lack a TSH-thyroid partnership capable of restoring their thyroid metabolic health?
Therefore, treated thyroid patients deserve an even deeper analysis of their progression through NTIS, including their LT4 and LT3 or desiccated thyroid therapy dosages, antibody status, and thyroid disease etiologies.
One can only hope that in a future publication, Anderson’s data tables of prevalence rates will be provided for this treated subset for all 10 diseases examined for the untreated population.
We need to know this population’s unique quartile divisions and their FT3:FT4 ratio data, not just see this population always presented through the lens of healthy-thyroid population statistical norms.
Consider that it is inappropriate to continually view a unique population through the lens of another population’s statistics. It’s like presenting women’s sex hormone data through the lens of men’s sex hormone statistical parameters, or presenting pregnant women’s thyroid hormone data always through the lens of non-pregnant women’s thyroid hormone statistical parameters.
And may long term LT3- and NDT/DTE-dosed populations also be included in future studies, to enable comparison of their disease prevalence rates with those on T4 monotherapy.
4. Call for a T3 paradigm shift in thyroid science
In 2014, the American Thyroid Association published a set of “Guidelines for the treatment of hypothyroidism” (Jonklaas et al, 2014).
This is what they had to say about T3 concentrations:
The ATA guideline quotation above is the opening of a section that attempts to minimize FT3 hormone testing recent studies of thyroid therapy. By calling T3 levels “mildly low,” “perturbations” and “variations,” it represents the only T3 fluctuations that are likely to occur as minimal in degree, and therefore implicitly minimal in clinical significance.
If you search the Jonklaas 2014 ATA guidelines for the word “unknown,” you will find it occurs 8 times in the document, and always in reference to T3 and to the enzymes that convert T4 to T3. No other aspect of hypothyroid therapy, apparently, is remarkable enough to warrant an emphatic declaration about its being unknown.
What a shameful admission of ignorance of our most potent thyroid hormone — and without any literature review of research on T3 hormone in chronic diseases during nonthyroidal illness syndrome.
It makes it appear that a repeated claim of research-based ignorance, poorly proven with a thorough search, is being used as justification to hold to a now traditional policy, since the 1990s, guarding against FT3 testing and optimization of FT3 levels in favor of testing only TSH and occasionally FT4.
How could they be so bold in claiming that there was nothing known?
Click to read more in-depth analysis
We need a paradigm shift.
The TSH-T4 paradigm has biased and blinded decades of thyroid research with unphysiological hormone hierarchies, omissions, and presumptions.
It has prevented our healthcare systems from seeing FT3 and the FT3:FT4 ratio’s far greater power over human health than mere TSH concentrations in or out of range.
It deceives some doctors and scientists into believing there is nothing known, and nothing worth knowing, about the way FT3, in relationship to FT4, can play a disease-modifying role in chronic cardiovascular, neurological, and metabolic disorders.
You’ve seen how strongly FT3 concentrations in and beyond range can associate with disease prevalence. You see that FT3:FT4 ratios can make some distinctions clearer.
It’s up to us to make a change. Refuse to accept the continued exclusion that separates the most vulnerable thyroid-disabled people from the most powerful thyroid hormone concentration, Free T3.
It’s time to renew the paradigm of thyroid therapy.
- Tania S. Smith
How to read the “category diagnoses” in the tables
Click to expand
Three types of Hypothyroidism
Three subtypes of hypothyroidism (including tissue hypothyroidism, NTIS) were found in three of Anderson et al’s hormone levels:
- Isolated Low FT4 level: Overt hypothyroidism, with a high FT3:FT4 ratio and high TSH.
- Highest TSH level: Overt hypothyroidism, but with a much lower FT3 and the highest average TSH.
- Isolated Low FT3 level: “Nonthyroidial illness syndrome,” (NTIS), or “Low T3 syndrome“.
Click to read the details on each
Three types of Hyperthyroidism
Three subtypes of hyperthyroidism were found within the opposite hormone level categories. The subtypes were associated with different FT3:FT4 ratios and levels:
- High FT4 level: Overt hyperthyroidism, with a moderate FT3:FT4 ratio
- Low TSH level: Subclinical hyperthyroidism, with high-normal thyroid hormones
- High FT3 level: Overt hyperthyroidism, with a high FT3:FT4 ratio.
Click to read the details on each
Why is the ratio of average FT3:FT4 important?
The ratio of FT3 to FT4 appears to be a basic principle in normal thyroid hormone economy when no thyroid hormone dosing and no thyroid disease interferes.
This ratio is an indicator of the normal or abnormal response of the individual’s thyroid gland and thyroid hormone metabolism to the level of TSH-receptor stimulation.
The ratio of FT3:FT4 can be judged low, normal, or high when expressed in pmol/L and compared with Gullo et al, 2011’s healthy control group of 3,875 people, and Strich et al, 2016’s study of 27,940 untreated patients at all ages.
- Gullo and team discovered that the average ratio among healthy controls is approximately 0.32-0.33 and the reference range was from 0.20 to 0.50.
- Anderson’s data set coincidentally fits almost perfectly with Gullo’s range and average. Mid-range ratios of average FT3:FT4 in the table are approximately 0.33 pmol/L. The lowest ratio was 0.24 and highest ratio was 0.53.
- Gullo found that this average ratio was constant across all normal levels of TSH in the healthy population.
- Anderson’s TSH normal quartiles coincidentally agree with Gullo’s finding; they express 0.33-0.34 ratio across the entire normal range.
- Strich found that the FT3:FT4 ratio decreased decade by decade from childhood to advanced age, but did not change much between age 30 and 60.
- Anderson’s ratio average within TSH Normal Q1-Q4 is 0.3325 and the average age of the population was 64.9 years.
- Strich et al’s ratio average within TSH Normal Q1-Q4 is 0.345 in the 60-70-year-olds category.
For advanced scientific readers: Learn how this ratio is adjusted in the human body
Click to read about differences in thyroid-disabled, treated patients
How to read the patterns in reference range
In the graphic above, each hormone’s set of 4 quartiles changes one hormone variable while holding another variable almost constant.
This makes each hormone category unique. It enriches the data set with diverse hormone profiles for comparison.
Such differences may give clues to help us understand, for example, why the disease prevalence rate for TSH in Q1 is different from FT4 in Q4.